Nuclear receptor corepressors partner with class II histone deacetylases in a Sin3-independent repression pathway

Transcriptional repression mediated by corepressors N-CoR and SMRT is a cri tical function of nuclear hormone receptors, and is dysregulated in human m yeloid leukemias. At the present time, these corepressors are thought to ac t exclusively through an mSin3/HDAC1 complex. Surprisingly, however, numero us biochemical studies have not detected N-CoR or SMRT in mSin3- and HDAC1- containing complexes. Each corepressor contains multiple repression domains (RDs), the significance of which is unknown. Here we show that these RDs a re nonredundant, and that one RD, which is conserved in N-CoR and SMRT, rep resses transcription by interacting directly with class II HDAC4 and HDAC5. Endogenous N-CoR and SMRT each associate with HDAC4 in a complex that does not contain mSin3A or HDAC1. This is the first example of a single corepre ssor utilizing distinct domains to engage multiple HDAC complexes. The alte rnative HDAC complexes may mediate specific repression pathways in normal a s well as leukemic cells.